A potent physiological method to magnify and sustain soleus oxidative metabolism improves glucose and lipid regulation.

Slow oxidative muscle, most notably the soleus, is inherently well equipped with the molecular machinery for regulating blood-borne substrates. However, the entire human musculature accounts for only ∼15% of the body's oxidative metabolism of glucose at the resting energy expenditure, despite being the body's largest lean tissue mass. We found the human soleus muscle could raise local oxidative metabolism to high levels for hours without fatigue, during a type of soleus-dominant activity while sitting, even in unfit volunteers. Muscle biopsies revealed there was minimal glycogen use. Magnifying the otherwise negligible local energy expenditure with isolated contractions improved systemic VLDL-triglyceride and glucose homeostasis by a large magnitude, e.g., 52% less postprandial glucose excursion (∼50 mg/dL less between ∼1 and 2 h) with 60% less hyperinsulinemia. Targeting a small oxidative muscle mass (∼1% body mass) with local contractile activity is a potent method for improving systemic metabolic regulation while prolonging the benefits of oxidative metabolism.

Sitting, squatting, and the evolutionary biology of human inactivity.

Recent work suggests human physiology is not well adapted to prolonged periods of inactivity, with time spent sitting increasing cardiovascular disease and mortality risk. Health risks from sitting are generally linked with reduced levels of muscle contractions in chair-sitting postures and associated reductions in muscle metabolism. These inactivity-associated health risks are somewhat paradoxical, since evolutionary pressures tend to favor energy-minimizing strategies, including rest. Here, we examined inactivity in a hunter-gatherer population (the Hadza of Tanzania) to understand how sedentary behaviors occur in a nonindustrial economic context more typical of humans' evolutionary history. We tested the hypothesis that nonambulatory rest in hunter-gatherers involves increased muscle activity that is different from chair-sitting sedentary postures used in industrialized populations. Using a combination of objectively measured inactivity from thigh-worn accelerometers, observational data, and electromygraphic data, we show that hunter-gatherers have high levels of total nonambulatory time (mean ± SD = 9.90 ± 2.36 h/d), similar to those found in industrialized populations. However, nonambulatory time in Hadza adults often occurs in postures like squatting, and we show that these "active rest" postures require higher levels of lower limb muscle activity than chair sitting. Based on our results, we introduce the Inactivity Mismatch Hypothesis and propose that human physiology is likely adapted to more consistently active muscles derived from both physical activity and from nonambulatory postures with higher levels of muscle contraction. Interventions built on this model may help reduce the negative health impacts of inactivity in industrialized populations.

The Necessity of Active Muscle Metabolism for Healthy Aging: Muscular Activity Throughout the Entire Day.

There is more need for "a movement-movement" than ever before. The percentage of seniors in our population is rising exponentially. Sedentary lifestyles throughout the lifespan have become the norm, including inactive youth and a sedentary workforce. Preventable chronic diseases caused by sedentary living have both lowered the quality of life for those directly affected or their families, and have created an unsustainable economic dilemma. In this article, we explain that whether it is a sedentary student, worker, or retiree, the most neglected but essential facts are as follows. By far, the most potent and rapid way to raise the rate of healthy metabolic and cardiovascular processes is through the immediate benefits of muscle contractions. Working muscle demands more energy and fuel than any other tissue in the body, but during inactivity the metabolic rate of muscle is relatively low. Depending on the type of contraction, muscle type, and other factors, the local fuel requirements within the working muscle can help to manage metabolic risks through a variety of processes, such as blood glucose utilization, uptake of unhealthy blood triglycerides, and increased blood flow. Given the large amount of time that people spend inactive each day, there is an enormous opportunity to raise the bar in optimizing health throughout the entire lifespan. Developed correctly, safe and low effort muscular activity can be performed for relatively long periods of time each day by the elderly and all segments of the population to optimize health and well being during aging.

What is the metabolic and energy cost of sitting, standing and sit/stand transitions?

PURPOSE: Modern lifestyles require people to spend prolonged periods of sitting, and public health messages recommend replacing sitting with as much standing as is feasible. The metabolic/energy cost (MEC) of sitting and standing is poorly understood, and MEC associated with a transition from sitting to standing has not been reported. Thus, we carefully quantified the MEC for sitting, standing and sit/stand transitions, adjusting for age and fat-free mass (FFM) in a sample of adults with no known disease. METHODS: Participants (N = 50; 25 women), 20­64 years, randomly performed three conditions for 10 min each (sitting, standing, 1 sit/stand transition min(−1) and then sitting back down). MEC was measured by indirect calorimetry and FFM by dual-energy X-ray absorptiometry. RESULTS: V̇O2 (ml kg(−1) min(−1)) for sitting (2.93 ± 0.61; 2.87 ± 0.37 in men and women respectively), standing (3.16 ± 0.63; 3.03 ± 0.40), and steady-state cost of repeated sit/stand transitions (1 min(−1)) (3.86 ± 0.75; 3.79 ± 0.57) were significantly different regardless of sex and weight (p < 0.001). EE (kcal min(−1)) also differed from sitting (1.14 ± 0.18; 0.88 ± 0.11), to standing (1.23 ± 0.19; 0.92 ± 0.13), and sit/stand transitions (1 min(−1)) (1.49 ± 0.25; 1.16 ± 0.16). Heart-rate increased from sitting to standing (~13 bpm; p < 0.001). Neither sex nor FFM influenced the results (p ≥ 0.05). CONCLUSIONS: This study found in a sample of adults with no known disease that continuous standing raised MEC 0.07 kcal min(−1) above normal sitting. The transition from sitting to standing (and return to sitting) had a metabolic cost of 0.32 kcal min(−1) above sitting. Therefore, public health messages recommending to interrupt sitting frequently should be informed of the modest energetic costs regardless of sex and body composition.

Intra-individual and inter-individual variability in daily sitting time and MVPA.

OBJECTIVES: Little is known about how much variability exists in free-living sitting time within individuals. The purpose of this study was to examine intra-individual variability of objectively determined daily sitting time and to determine if this variability was related to weekly averages of sitting duration or recommended moderate-vigorous physical activity (MVPA). Also, this study determined the reliability of free-living sitting and MVPA time as it useful for guiding researchers in determining how many days of monitoring are needed. DESIGN: An activPAL monitor was worn for 7 consecutive days by 68 women (52±8 years). METHODS: Intra-individual range of daily sitting time was calculated. Generalizability theory analysis determined the reliability of daily sitting and recommended MVPA. RESULTS: Mean sitting time was 9.0±1.8h/day and the within individual weekly mean range was 4.5±1.7h/day. Similarly, there was a 4.5h/day difference in sitting time between the mean of the lowest sitting (6.7±0.8) and highest sitting (11.3±1.1h/day) quartiles. The intra-individual range in daily sitting did not differ among quartiles of sitting time (i.e., 4.9±1.9, 4.1±1.9, 5.1±1.5, 3.9±1.1h/day for the 1st-4th quartiles) nor among quartiles of MVPA (i.e., 4.2±1.8, 4.7±2.0, 4.6±1.5, 4.4±1.3h/day for the 1st-4th quartiles). A reliability coefficient of 0.80 was achieved with 4 days of objectively measured sitting time and 7 days for MVPA. CONCLUSIONS: The findings suggest exposure to relatively high levels of sedentary time may occur in people regardless of weekly averages in sitting and regular exercise due to the high day-to-day variation in daily sitting time (4.5h/d range within a week).

Free-living activity counts-derived breaks in sedentary time: Are they real transitions from sitting to standing?

BACKGROUND: Previous research has demonstrated a link between free-living accelerometer-measured breaks in sedentary time and health related variables. Breaks in sedentary time are typically inferred from time-stamped accelerometer data indicating a transition from lack of movement (recording of <100 activity counts/min) to relatively more movement (≥100 activity counts/min). However, it remains unknown whether these breaks actually represent sit-to-stand postural transitions in free-living. Thus, the purpose of this study was to compare free-living accelerometer-derived and posture-derived estimates of breaks in sedentary time using the ActiGraph GT3X+ (AG) and the activPAL™ (AP), respectively. METHODS: A total of 15 participants concurrently wore an AG at their waist and an AP on their right thigh for 7 consecutive days (24h/day - removing them only when in contact with water). Data from both devices were matched on minute-by-minute timestamps while also applying a 3-min allowance window to account for clock drift. Dependent t-test was used to evaluate differences in mean breaks between AG and AP. RESULTS: The AG detected 74±4.1 breaks/day (mean±SEM) while the AP detected 39±3.1 breaks/day (P<0.001). On average, the AG detected 67% of the AP breaks while 65% of the AG breaks did not correspond with AP breaks. Of the non-corresponding AG breaks, 52% occurred when participants were sitting, 42% when standing, and 6% when transitioning from standing to sitting. CONCLUSION: The AG detected a significantly higher number of breaks in sedentary time, the majority of which do not correspond to sit-to-stand transitions as measured by the AP.

Sedentary behavior as a mediator of type 2 diabetes.

Over the past 5 years, the fastest growing new area of physical activity research centered around the concept that the large amount of time people spend sitting inactive may have significant physiological consequences hazardous to human health, including risk for type 2 diabetes and poor metabolism of lipids and glucose. Meta-analysis (10 studies) suggests there is a 112% greater relative risk associated with a large duration of sedentary behavior for type 2 diabetes. Meta-analysis also indicates significantly greater odds for metabolic syndrome. We also summarize results for 7 studies using objective measures of total sedentary time and focusing on cardiometabolic risks in persons at high risk for type 2 diabetes or already diagnosed with type 2 diabetes. The underlying hypothesis introduced in 2004 by the inactivity physiology paradigm has been that frequent and abundant contractile activity by certain types of skeletal muscle can have a potent influence on key physiological processes, even when the intensity is below that achieved through exercise. We explain some of the mechanisms for why the metabolism in slow-twitch oxidative skeletal muscle is key for understanding the healthy responses to low-intensity physical activity (LIPA). Findings from objective measures from inclinometry indicated that the quartile range for weekly sedentary time is ∼29 h/week. The total daily time that people sit, stand, and accumulate nonexercise steps is independent of traditionally recommended moderate-vigorous physical activity. The large amount of sedentary time associated with risk for disease can only be reduced significantly with safe and nonfatiguing LIPA, especially in the most at-risk proportion of the population. Importantly, experimental studies are starting to indicate that it will be especially insightful to understand the acute dose-response effects of LIPA in order to understand why reducing sedentary time can improve lipid and glucose metabolism for the prevention and treatment of chronic disorders related to type 2 diabetes.

Short-term overeating results in incomplete energy intake compensation regardless of energy density or macronutrient composition.

OBJECTIVE: To evaluate the effects of overeating (140% of energy requirements) a high-fat low-energy density diet (HF/LED, 1.05 kcal/g), high-fat high-energy density diet (HF/HED, 1.60 kcal/g), and high-carbohydrate (HC) LED (1.05 kcal/g) for 2-days on subsequent 4-day energy intake (EI), activity levels, appetite, and mood. DESIGN AND METHODS: Using a randomized cross-over design, energy expenditure and EI were standardized during overeating. RESULTS: In 20 adults with a mean ± SD BMI of 30.7 ± 4.6 kg/m(2) , EI was not suppressed until the second day after overeating and accounted for ∼30% of the excess EI. Reductions in EI did not differ among the three diets or across days. Overeating had no effect on subsequent energy expenditure but steps/day decreased after the HC/LED and HF/HED. Sleep time was increased after the HF/HED compared to both LEDs. After overeating a HF/HED vs. HF/LED, carbohydrate cravings, hunger, prospective food consumption, and sadness increased and satisfaction, relaxation, and tranquility decreased. CONCLUSIONS: Diet type, time, or their interaction had no impact on compensation over 4 days. No adaptive thermogenesis was observed. The HF/HED vs. HF/LED had detrimental effects on food cravings, appetite, and mood. These results suggest short-term overeating is associated with incomplete compensation.

Evidence that women meeting physical activity guidelines do not sit less: an observational inclinometry study.

BACKGROUND: The inactivity physiology paradigm proposes that sedentary behaviors, including sitting too much, are independent of the type of physical activity delineated for health in the Physical Activity Guidelines for Americans. Thus, we hypothesized that, when accounting for behaviors across the entire day, variability in the amount of time spent sitting would be independent of the inter-and intra-individual time engaged in sustained moderate-to-vigorous physical activity (MVPA). METHODS: Ninety-one healthy women, aged 40-75 years, completed a demographic questionnaire and assessment of height and weight. Participants wore the activPAL activity monitor for one week and time (minutes/day) spent sitting, standing, stepping, and in sustained bouts (bouts ≥10 minutes) of MVPA were quantified. The women were then stratified into groups based on weekly sustained MVPA. Additionally, each day of data collection for each participant was classified as either a "sufficient" MVPA day (≥ 30 min of MVPA) or an "insufficient" MVPA day for within-participant analyses. RESULTS: Time spent sitting, standing, and in incidental non-exercise stepping averaged 64, 28, and 11 hrs/week, respectively, and did not differ between groups with individuals meeting/exceeding the current exercise recommendation of 150 min/week of sustained MVPA in ≥10 minutes bouts (M = 294 min/week, SD = 22) compared to those with none or minimal levels (M= 20 min/week, SD = 4). Time spent sitting (M = 9.1 hr/day, SD = 0.19 vs. M = 8.8 hr/day, SD = 0.22), standing (M = 3.9 hr/day, SD = 0.16 vs. M = 3.9 hr/day, SD = 0.15), and in intermittent stepping (M = 1.6 hr/day, SD = 0.07 vs. M = 1.6 hr/day, SD = 0.06) did not differ between days with (~55 min/day) and without recommended MVPA. CONCLUSIONS: This study provides the first objective evidence that participation in sustained MVPA is unrelated to daily sitting duration in relatively healthy, middle and older-aged women. More research is needed to extend these findings to other populations and to inform distinct behavioral recommendations focused on sedentary time.

Identification of hemostatic genes expressed in human and rat leg muscles and a novel gene (LPP1/PAP2A) suppressed during prolonged physical inactivity (sitting).

BACKGROUND: Partly because of functional genomics, there has been a major paradigm shift from solely thinking of skeletal muscle as contractile machinery to an understanding that it can have roles in paracrine and endocrine functions. Physical inactivity is an established risk factor for some blood clotting disorders. The effects of inactivity during sitting are most alarming when a person develops the enigmatic condition in the legs called deep venous thrombosis (DVT) or "coach syndrome," caused in part by muscular inactivity. The goal of this study was to determine if skeletal muscle expresses genes with roles in hemostasis and if their expression level was responsive to muscular inactivity such as occurs in prolonged sitting. METHODS: Microarray analyses were performed on skeletal muscle samples from rats and humans to identify genes associated with hemostatic function that were significantly expressed above background based on multiple probe sets with perfect and mismatch sequences. Furthermore, we determined if any of these genes were responsive to models of physical inactivity. Multiple criteria were used to determine differential expression including significant expression above background, fold change, and non-parametric statistical tests. RESULTS: These studies demonstrate skeletal muscle tissue expresses at least 17 genes involved in hemostasis. These include the fibrinolytic factors tetranectin, annexin A2, and tPA; the anti-coagulant factors TFPI, protein C receptor, PAF acetylhydrolase; coagulation factors, and genes necessary for the posttranslational modification of these coagulation factors such as vitamin K epoxide reductase. Of special interest, lipid phosphate phosphatase-1 (LPP1/PAP2A), a key gene for degrading prothrombotic and proinflammatory lysophospholipids, was suppressed locally in muscle tissue within hours after sitting in humans; this was also observed after acute and chronic physical inactivity conditions in rats, and exercise was relatively ineffective at counteracting this effect in both species. CONCLUSIONS: These findings suggest that skeletal muscle may play an important role in hemostasis and that muscular inactivity may contribute to hemostatic disorders not only because of the slowing of blood flow per se, but also potentially because of the contribution from genes expressed locally in muscles, such as LPP1.

Lipoprotein particle distribution and skeletal muscle lipoprotein lipase activity after acute exercise.

BACKGROUND: Many of the metabolic effects of exercise are due to the most recent exercise session. With recent advances in nuclear magnetic resonance spectroscopy (NMRS), it is possible to gain insight about which lipoprotein particles are responsible for mediating exercise effects. METHODS: Using a randomized cross-over design, very low density lipoprotein (VLDL) responses were evaluated in eight men on the morning after i) an inactive control trial (CON), ii) exercising vigorously on the prior evening for 100 min followed by fasting overnight to maintain an energy and carbohydrate deficit (EX-DEF), and iii) after the same exercise session followed by carbohydrate intake to restore muscle glycogen and carbohydrate balance (EX-BAL). RESULTS: The intermediate, low and high density lipoprotein particle concentrations did not differ between trials. Fasting triglyceride (TG) determined biochemically, and mean VLDL size were lower in EX-DEF but not in EX-BAL compared to CON, primarily due to a reduction in VLDL-TG in the 70-120 nm (large) particle range. In contrast, VLDL-TG was lower in both EX-DEF and EX-BAL compared to CON in the 43-55 nm (medium) particle range. VLDL-TG in smaller particles (29-43 nm) was unaffected by exercise. Because the majority of VLDL particles were in this smallest size range and resistant to change, total VLDL particle concentration was not different between any of these conditions. Skeletal muscle lipoprotein lipase (LPL) activity was also not different across these 3 trials. However, in CON only, the inter-individual differences in LPL activity were inversely correlated with fasting TG, VLDL-TG, total, large and small VLDL particle concentration and VLDL size, indicating a regulatory role for LPL in the non-exercised state. CONCLUSIONS: These findings reveal a high level of differential regulation between different sized triglyceride-rich lipoproteins following exercise and feeding, in the absence of changes in LPL activity.

Appetite regulation in response to sitting and energy imbalance.

The impact of sitting and energy imbalance on appetite and appetite-regulating hormones (acylated ghrelin and leptin) was assessed in response to 1 day of sitting, with and without changes in energy intake. Fourteen men and women completed each of three 24-h conditions: high energy expenditure (standing) with energy balance (STAND), low energy expenditure (sitting) with energy surplus (SIT), and sitting with energy balance (SIT-BAL). Ghrelin, leptin, and appetite were measured in the fasted state and following a standardized meal. In the fasted state, there were no differences among conditions. Following the meal, ghrelin was lower in SIT than in STAND, with no change in appetite. When intake was reduced (SIT-BAL), the decrease in ghrelin when sitting was attenuated, hunger increased, and fullness decreased. SIT led to lower ghrelin concentrations in the men, whereas in the women, leptin increased. SIT-BAL led to an increase in ghrelin in the men but attenuated the leptin response, reduced ghrelin, increased hunger, and decreased fullness in the women. Because a dramatic reduction in energy expenditure was not accompanied by reduced appetite, prolonged sitting may promote excess energy intake, leading to weight gain in both men and women.

Impact of exercise training on endothelial transcriptional profiles in healthy swine: a genome-wide microarray analysis.

While the salutary effects of exercise training on conduit artery endothelial cells have been reported in animals and humans with cardiovascular risk factors or disease, whether a healthy endothelium is alterable with exercise training is less certain. The purpose of this study was to evaluate the impact of exercise training on transcriptional profiles in normal endothelial cells using a genome-wide microarray analysis. Brachial and internal mammary endothelial gene expression was compared between a group of healthy pigs that exercise trained for 16-20 wk (n = 8) and a group that remained sedentary (n = 8). We found that a total of 130 genes were upregulated and 84 genes downregulated in brachial artery endothelial cells with exercise training (>1.5-fold and false discovery rate <15%). In contrast, a total of 113 genes were upregulated and 31 genes downregulated in internal mammary artery endothelial cells using the same criteria. Although there was an overlap of 66 genes (59 upregulated and 7 downregulated with exercise training) between the brachial and internal mammary arteries, the identified endothelial gene networks and biological processes influenced by exercise training were distinctly different between the brachial and internal mammary arteries. These data indicate that a healthy endothelium is indeed responsive to exercise training and support the concept that the influence of physical activity on endothelial gene expression is not homogenously distributed throughout the vasculature.

Effects of 1 day of inactivity on insulin action in healthy men and women: interaction with energy intake.

Prolonged periods of limited muscle activity can reduce insulin action. Acute changes in low muscle activity (ie, sitting) have not been assessed. In addition, unless energy intake is reduced during sitting to match low expenditure, the concurrent energy surplus may explain lower insulin action. The objective of the study was to evaluate the acute effect of sitting, with and without energy surplus, on insulin action. Fourteen young (26.1 ± 4.5 years, mean ± SD), nonobese (23.7% ± 7.1% fat), fit (peak oxygen consumption = 49.1 ± 3.3 mL·kg(-1)·min(-1)) men (n = 7) and women (n = 7) completed three 24-hour conditions: (1) an active, no-sitting condition (high energy expenditure of 2944 ± 124 kcal with energy intake matched to expenditure) = NO-SIT; (2) low energy expenditure (sitting) of 2195 ± 121 kcal with no reduction in energy intake (energy surplus) = SIT; and (3) sitting with energy intake reduced to 2139 ± 118 kcal to match low expenditure (energy balance) = SIT-BAL. Insulin action was measured the following morning during a continuous infusion of [6,6-(2)H]-glucose. Data were analyzed using linear mixed-effects models with planned contrasts. Compared with NO-SIT, insulin action, defined as whole-body rate of glucose disappearance normalized to mean plasma insulin, was reduced by 39% in SIT (P < .001) and by 18% in SIT-BAL (P = .07). Insulin action was higher in SIT-BAL compared with SIT (P = .04). One day of sitting considerably reduced insulin action; this effect was minimized, but not prevented, when energy intake was reduced to match expenditure. Strategies to limit daily sitting may reduce metabolic disease risk.

Influence of acute exercise with and without carbohydrate replacement on postprandial lipid metabolism.

Acute exercise, undertaken on the day before an oral fat tolerance test (OFTT), typically reduces postprandial triglycerides (TG) and increases high-density lipoprotein-cholesterol (HDL-C). However, the benefits of acute exercise may be overstated when studies do not account for compensatory changes in dietary intake. The objective of this study was to determine the influence of acute exercise, with and without carbohydrate (CHO) replacement, on postprandial lipid metabolism. Eight recreationally active young men underwent an OFTT on the morning after three experimental conditions: no exercise [control (Con)], prolonged exercise without CHO replacement (Ex-Def) and prolonged exercise with CHO replacement to restore CHO and energy balance (Ex-Bal). The exercise session in Ex-Def and Ex-Bal consisted of 90 min cycle ergometry at 70% peak oxygen uptake (Vo(2peak)) followed by 10 maximal 1-min sprints. CHO replacement was achieved using glucose solutions consumed at 0, 2, and 4 h postexercise. Muscle glycogen was 40 +/- 4% (P < 0.05) and 94 +/- 3% (P = 0.24) of Con values on the morning of the Ex-Def and Ex-Bal OFTT, respectively. Postprandial TG were 40 +/- 14% lower and postprandial HDL-C, free fatty acids, and 3-hydroxybutyrate were higher in Ex-Def compared with Con (P < 0.05). Most importantly, these exercise effects were not evident in Ex-Bal. Postprandial insulin and glucose and the homeostatic model assessment of insulin resistance (HOMA(IR)) were not significantly different across trials. There was no relation between the changes in postprandial TG and muscle glycogen across trials. In conclusion, the influence of acute exhaustive exercise on postprandial lipid metabolism is largely dependent on the associated CHO and energy deficit.

Too Little Exercise and Too Much Sitting: Inactivity Physiology and the Need for New Recommendations on Sedentary Behavior.

Moderate- to vigorous-intensity physical activity has an established preventive role in cardiovascular disease, type 2 diabetes, obesity, and some cancers. However, recent epidemiologic evidence suggests that sitting time has deleterious cardiovascular and metabolic effects that are independent of whether adults meet physical activity guidelines. Evidence from "inactivity physiology" laboratory studies has identified unique mechanisms that are distinct from the biologic bases of exercising. Opportunities for sedentary behaviors are ubiquitous and are likely to increase with further innovations in technologies. We present a compelling selection of emerging evidence on the deleterious effects of sedentary behavior, as it is underpinned by the unique physiology of inactivity. It is time to consider excessive sitting a serious health hazard, with the potential for ultimately giving consideration to the inclusion of too much sitting (or too few breaks from sitting) in physical activity and health guidelines.

Role of low energy expenditure and sitting in obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease.

It is not uncommon for people to spend one-half of their waking day sitting, with relatively idle muscles. The other half of the day includes the often large volume of nonexercise physical activity. Given the increasing pace of technological change in domestic, community, and workplace environments, modern humans may still not have reached the historical pinnacle of physical inactivity, even in cohorts where people already do not perform exercise. Our purpose here is to examine the role of sedentary behaviors, especially sitting, on mortality, cardiovascular disease, type 2 diabetes, metabolic syndrome risk factors, and obesity. Recent observational epidemiological studies strongly suggest that daily sitting time or low nonexercise activity levels may have a significant direct relationship with each of these medical concerns. There is now a need for studies to differentiate between the potentially unique molecular, physiologic, and clinical effects of too much sitting (inactivity physiology) separate from the responses caused by structured exercise (exercise physiology). In theory, this may be in part because nonexercise activity thermogenesis is generally a much greater component of total energy expenditure than exercise or because any type of brief, yet frequent, muscular contraction throughout the day may be necessary to short-circuit unhealthy molecular signals causing metabolic diseases. One of the first series of controlled laboratory studies providing translational evidence for a molecular reason to maintain high levels of daily low-intensity and intermittent activity came from examinations of the cellular regulation of skeletal muscle lipoprotein lipase (LPL) (a protein important for controlling plasma triglyceride catabolism, HDL cholesterol, and other metabolic risk factors). Experimentally reducing normal spontaneous standing and ambulatory time had a much greater effect on LPL regulation than adding vigorous exercise training on top of the normal level of nonexercise activity. Those studies also found that inactivity initiated unique cellular processes that were qualitatively different from the exercise responses. In summary, there is an emergence of inactivity physiology studies. These are beginning to raise a new concern with potentially major clinical and public health significance: the average nonexercising person may become even more metabolically unfit in the coming years if they sit too much, thereby limiting the normally high volume of intermittent nonexercise physical activity in everyday life. Thus, if the inactivity physiology paradigm is proven to be true, the dire concern for the future may rest with growing numbers of people unaware of the potential insidious dangers of sitting too much and who are not taking advantage of the benefits of maintaining nonexercise activity throughout much of the day.

Physical inactivity amplifies the sensitivity of skeletal muscle to the lipid-induced downregulation of lipoprotein lipase activity.

Physical inactivity is a risk factor for lipoprotein disorders and the metabolic syndrome. Physical inactivity has a powerful effect on suppressing lipoprotein lipase (LPL) activity in skeletal muscle, the rate-limiting enzyme for hydrolysis of triglyceride (TG)-rich lipoproteins. We tested the ability of several compounds to prevent the decrease in LPL. The present study minimized standing and ordinary light nonexercise movements in rats to compare the effects of inactivity and nonexercise activity thermogenesis (NEAT) on LPL activity. The key new insight was that the typically quick decrease in LPL activity of oxidative muscle caused by physical inactivity was prevented by nicotinic acid (NA), whereas inhibitors of TNF-alpha, inducible nitric oxide synthase, and NF-kappaB had no such effect. NA was administered at a dose known to acutely impede the appearance of plasma TG from the liver and free fatty acids from adipose tissue, and it was effective at intentionally lowering plasma lipid concentrations to the same level in active and inactive groups. As measured from heparin-releasable LPL activity, LPL in the microvasculature of the most oxidative muscles was approximately 90% lower in the inactive group compared with controls, and this suppression was completely blocked by NA. In contrast to inactivity, NA did not raise muscle LPL in ambulatory controls, whereas a large exogenous fat delivery did decrease LPL activity. In vitro control studies revealed that NA did not have a direct effect on skeletal muscle LPL activity. In conclusion, physical inactivity amplifies the ability of plasma lipids to suppress muscle LPL activity. The light ambulatory contractions responsible for NEAT are sufficient for mitigating these deleterious effects.

Exercise physiology versus inactivity physiology: an essential concept for understanding lipoprotein lipase regulation.

Some health-related proteins such as lipoprotein lipase may be regulated by qualitatively different processes over the physical activity continuum, sometimes with very high sensitivity to inactivity. The most powerful process known to regulate lipoprotein lipase protein and activity in muscle capillaries may be initiated by inhibitory signals during physical inactivity, independent of changes in lipoprotein lipase messenger RNA.

Manipulation of dietary carbohydrate and muscle glycogen affects glucose uptake during exercise when fat oxidation is impaired by beta-adrenergic blockade.

We have recently reported that, during moderate intensity exercise, low muscle glycogen concentration and utilization caused by a high-fat diet is associated with a marked increase in fat oxidation with no effect on plasma glucose uptake (R(d) glucose). It is our hypothesis that this increase in fat oxidation compensates for low muscle glycogen, thus preventing an increase in R(d) glucose. Therefore, the purpose of this study was to determine whether low muscle glycogen availability increases R(d) glucose under conditions of impaired fat oxidation. Six cyclists exercised at 50% peak O(2) consumption (Vo(2 peak)) for 1 h after 2 days on either a high-fat (HF, 60% fat, 24% carbohydrate) or control (CON, 22% fat, 65% carbohydrate) diet to manipulate muscle glycogen to low and normal levels, respectively. Two hours before the start of exercise, subjects ingested 80 mg of propanolol (betaB), a nonselective beta-adrenergic receptor blocker, to impair fat oxidation during exercise. HF significantly decreased calculated muscle glycogen oxidation (P < 0.05), and this decrease was partly compensated for by an increase in fat oxidation (P < 0.05), accompanied by an increase in whole body lipolysis (P < 0.05), despite the presence of betaB. Although HF increased fat oxidation, plasma glucose appearance rate, R(d) glucose, and glucose clearance rate were also significantly increased by 13, 15, and 26%, respectively (all P < 0.05). In conclusion, when lipolysis and fat oxidation are impaired, in this case by betaB, fat oxidation cannot completely compensate for a reduction in muscle glycogen utilization, and consequently plasma glucose turnover increases. These findings suggest that there is a hierarchy of substrate compensation for reduced muscle glycogen availability after a high-fat, low-carbohydrate diet, with fat being the primary and plasma glucose the secondary compensatory substrate. This apparent hierarchy likely serves to protect against hypoglycemia when endogenous glucose availability is low.